Semin Immunopathol DOI 10.1007/s00281-015-0488-2

REVIEW

New discoveries in CRMO: IL-1β, the neutrophil, and the microbiome implicated in disease pathogenesis in Pstpip2-deficient mice Polly J. Ferguson 1 & Ronald M. Laxer 2

Received: 28 February 2015 / Accepted: 31 March 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are autoinflammatory disorder(s) in which sterile osteomyelitis is frequently accompanied by inflammatory conditions of the joints, skin, or intestine. Patients with CRMO commonly have a personal or family history of psoriasis, inflammatory bowel disease, and inflammatory arthritis, suggesting shared disease pathogenesis. Work by our group and others has demonstrated that dysregulation of interleukin-1 (IL-1) signaling can drive sterile osteomyelitis in the two human monogenic forms of the disease. Recent work in the chronic multifocal osteomyelitis (cmo) mouse model demonstrates that the disease is IL-1-mediated, that neutrophils are critical effector cells and that both caspase-1 and caspase-8 play redundant roles in mediating the cleavage of pro-IL-1β into its biologically active form. Recent data in the cmo mouse demonstrate that dietary manipulation alters the cmo microbiome and can prevent the development of osteomyelitis. Further investigation is needed to determine the specific components of the diet that result in protection from disease and if this finding can be translated into a treatment for human CRMO. This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases - Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen * Polly J. Ferguson [email protected] 1

Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA

2

Division of Rheumatology, The Hospital for Sick Children and the University of Toronto, Toronto ON, Canada

Keywords Chronic recurrent multifocal osteomyelitis . Pstpip2 . Chronic non-bacterial osteomyelitis . Autoinflammatory . Interleukin-1 beta

Chronic non-bacterial osteomyelitis (CNO), chronic recurrent multifocal osteomyelitis (CRMO), and synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome are rare inflammatory disorder(s) in which destructive sterile bone inflammation is frequently accompanied by inflammatory disorders of the joints, skin, or intestine [1–4]. CRMO and SAPHO may be the same disease (the term CRMO is utilized by pediatric rheumatologists, whereas adult rheumatologists utilize the term SAPHO syndrome) with slightly different manifestations depending on age or perhaps they are distinct disorders affecting the same immunologic pathway. CRMO presents with bone pain due to sterile osteomyelitis. It can affect only one bone (CNO) or more often, multiple bones (CRMO) [3, 5–7]. There is frequently a personal or family history of inflammatory conditions of the joints, skin, or intestine [3, 8], most often a form of psoriasis or inflammatory bowel disease [9–17]. For the purpose of this review, we will predominately utilize the term “CRMO” and review significant advances in the understanding of non-bacterial osteomyelitis that have occurred in the past year. For the majority of individuals with CRMO, the genetic factors, immunologic pathways, and environmental triggers that are critical in disease initiation are unknown. An aberrant response to microbes, particularly Propionibacterium acnes, has been postulated in some adults with SAPHO syndrome [18–20]; however, in CRMO, bone cultures are typically sterile, antibiotic therapy is usually ineffective, and antiinflammatory medications result in improvement [3, 7, 21–30]. Treatment of CRMO varies depending on disease severity and chronicity. Non-steroidal anti-inflammatory

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medications and corticosteroids provide relief of pain for many patients [3, 6, 7], but others have unrelenting inflammation requiring off-label use of empiric therapies including tumor necrosis factor alpha (TNF-α) blockers [3, 17, 31] and bisphosphonates [32–38] with variable responses to therapy. Diagnosis is often delayed because there is no diagnostic test and inflammatory markers are often normal. Identification of the genetic etiology and molecular mechanisms required for the development of non-syndromic CRMO is needed to improve diagnosis and to guide therapy. Immunologic abnormalities of innate immunity have been described in CRMO and SAPHO. Multiple investigators have documented increased pro-inflammatory cytokines in the peripheral blood of affected individuals especially after in vitro stimulation of peripheral blood mononuclear cells (PBMC) to innate immune system triggers [3, 39–41]. Disruption of immunologic homeostasis resulting in enhanced proinflammatory responses occurs but the reason why the bone is the target remains unknown. Hofmann et al., found that LPS stimulated CNO PBMC, secreted significantly less IL-10, had attenuated extracellular signal-regulated kinase (ERK) 1/2 activity, and reduced levels of Sp-1, a transcription factor that drives IL-10 gene expression in monocytes [39–41]. This is associated with reduced histone H3 serine-10 phosphorylation suggesting that epigenetic factors play a role in the decreased gene expression of IL-10 seen in CNO [39]. They concluded that impaired mitogen-activated protein kinase (MAPK) signaling, decreased H3S10 phosphorylation, and attenuated Sp1 recruitment to the IL-10 promoter result in impaired gene expression of IL-10 with subsequent disruption of the pro- and anti-inflammatory cytokine balance [40]. There is strong evidence that CRMO can have a genetic basis. There are reports of affected sib-pairs and affected parent-child duos [3, 42, 43]. A susceptibility locus has been mapped to human chromosome 18q21.3–18q22 in a small German cohort [43]. There is a strikingly similar disease in dogs called hypertrophic osteodystrophy (HOD) that tends to cluster in litters in several large breed inbred dogs including Weimeraners [44]. The dogs develop sterile osteomyelitis in the first year of life which responds at least partially to treatment with corticosteroids. The affected dogs have also been reported to develop pustulosis and some develop Crohn’s disease making it an excellent model of human disease [44]. An initial report of linkage to the dog leukocyte antigen (DLA) locus could not be reproduced [44–46]. Although presumed to have a genetic basis, the precise gene(s) involved has yet to be identified. There are two mouse models of CRMO, the chronic multifocal osteomyelitis (cmo) which is a spontaneous mutant and the lupo mouse which was made by ENU mutagenesis [47, 48]. Disease in both mouse lines is caused by homozygous mutations in Pstpip2 [47, 48]. The mice have elevated proinflammatory cytokines in the blood, develop sterile

multifocal osteomyelitis and extramedullary hematopoiesis, and can develop inflammation of the skin [47–51]. Bone marrow transplants in the cmo mice revealed that the disease is hematopoietically driven, and studies in Rag1-deficient cmo mice demonstrated that the adaptive immune system is not needed for the disease [51]. And finally, there are two human forms of the CRMO that are due to single gene mutations including Majeed syndrome (mutations in LPIN2) and deficiency of the interleukin-1 receptor antagonist (DIRA, due to mutations in IL-1 RN) [52–55]. Majeed syndrome is an autosomal recessive disorder due to mutations in LPIN2 that presents with early onset CRMO (prior to the second year of life), a congenital dyserythropoietic anemia and, in some, a neutrophilic dermatosis (Sweet syndrome) [52, 55–57]. The affected individuals have systemic inflammation accompanied by failure to thrive, delayed puberty, and hepatosplenomegaly [56, 57]. Treatment with NSAIDs or corticosteroids produces only incomplete control of the disease [55–58]. There is clinical evidence that Majeed syndrome is an interleukin-1 beta (IL-1β) mediated disease as treatment of individuals with IL-1β blocking agents, but not TNF-α blocking agents, results in normalization of their inflammatory markers and resolution of bone inflammation [59]. LPIN2 is a phosphatidate phosphatase (PAP) that plays an important role in lipid metabolism [60, 61]. The Majeed syndrome associated mutation S734L disrupts PAP activity [61]. Saturated fatty acids are known innate immune system triggers [62–64]. Human and mouse monocytes stimulated with high levels of saturated fatty acids produce excessive amount of inflammatory cytokines when LPIN2 is under-expressed, whereas, monocytes that overexpress LPIN2 produce lower levels of inflammatory cytokines [65]. These findings suggest that an abnormal innate immune system response to fatty acids may play a role in the pathogenesis of Majeed syndrome and its associated inflammatory bony lesions. However, no abnormalities in lipid profiles have been found in children with Majeed syndrome. DIRA presents with severe systemic inflammation, destructive sterile bone disease (osteitis and periostitis), and sterile pustulosis of the skin [53, 54, 66]. If left undiagnosed and untreated, it is a potentially fatal disease with most reported deaths resulting from systemic inflammatory response syndrome and respiratory failure [53]. In patients with DIRA, there is unequivocal evidence that unfettered IL-1 signaling due to the absence of functional IL-1Ra, the key antagonist of the IL-1 receptor (IL-1R), leads to the development of sterile bone inflammation [53, 54]. Treatment with the recombinant IL-1 receptor antagonist (rIL-1Ra) results in prompt and, in most cases, complete control of all aspects of the disease including changes in the bone and skin [53, 54, 66]. Although no human has been identified with mutations in Pstpip2, significant advances in our understanding of sterile osteomyelitis have occurred by studying the Pstpip2-deficient

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cmo mouse. In the past year, two groups have demonstrated that IL-1β is a critical cytokine in the pathogenesis of osteomyelitis in the cmo mouse. Utilizing a genetic approach, both groups found that the cmo mice were completely protected from the development of osteomyelitis if the cmo mice lacked a functional IL-1 receptor I (IL-1RI) [49, 50]. In addition, it has been shown that IL-1β and not IL-1α is responsible for mediating the disease as IL-1α-deficient cmo mice develop disease with the same severity and timing as the cmo mice, but the cmo mice lacking IL-1β either had attenuated and delayed disease [49] or were completely protected from the disease [50]. IL-1β must be processed to become biologically active. In order to become active, the biologically inactive pro-IL-1β precursor protein must be cleaved into its mature, biologically active form and then secreted outside the cell. This classically involves the macromolecular Nlrp3 inflammasome complex with a cleavage occurring via the protease caspase-1 [67]. Given that IL-1β is critical to cmo disease pathogenesis, a series of cmo mice were produced that lacked key molecules in the Nlrp3 inflammasome including Nlrp3 (also known as cryopyrin), Asc, or caspase-1. These experiments demonstrated that the disease in the cmo mouse is not an Nlrp3 inflammasomopathy as the cmo mice deficient in any of Nlrp3, Asc, or caspase-1 developed the disease with the same timing and severity as occurs in the cmo mouse [49, 50]. These results suggest that another protease, besides caspase1, is involved in the cleavage and processing of pro-IL-1β into its biologically active form in the cmo mouse. Neutrophil serine proteases and caspase-8 have previously been shown to be able to perform this cleavage and opened up the possibility that the neutrophil may be important in the disease [67]. Cassel et al. performed a series of experiments designed to determine which innate immune system cell is critical for the enhanced IL-1β responses to innate immune system triggers in the cmo mouse. They found that LPS-primed cmo bone marrow cells, but not cmo bone marrow derived macrophages, hyperproduce IL-1β when triggered with ATP, silica, or Pseudomonas aeruginosa PAK strain [49]. IL-1β hypersecretion was also demonstrated in neutrophils isolated by Percoll gradient centrifugation that were then LPS-primed and triggered with silica [49]. They went on to show that IL-1β production could be significantly reduced if cmo bone marrow was treated with the serine protease inhibitor diisopropylfluorophosphate but was not reduced when treated with the caspase-1 inhibitor

z-YVAD-fmk [49]. These results implicate the neutrophil in the pathogenesis of cmo and suggest that a serine protease may be involved in the processing of pro-IL-1β into its biologically active form. Lukens et al. confirmed that the neutrophil and not bone marrow macrophages hypersecrete IL-1β when LPS-primed and stimulated with either ATP or silica and showed that pharmacologic depletion of neutrophils using the monoclonal antibody anti-Ly6G protected cmo mice from the development of the disease [68]. They produced cmo mutant mice that lacked key serine proteases elastase and proteinase 3 and found that neither enzyme is required for the development of osteomyelitis in this model [68]. They showed that the cmo mice that lack either caspase-1 or caspase-8 develop the disease, whereas the cmo mice that lack both caspases are protected from the disease suggesting that they play redundant roles in cmo disease pathogenesis [68]. Lukens et al. performed an intriguing set of experiments demonstrating that dietary manipulation resulting in changes in the microbiome can prevent the development of osteomyelitis in the cmo mouse. They found that the cmo mice fed with a high fat diet (HFD) were protected from the development of clinical, radiological, and histological evidence of osteomyelitis [68]. The HFD-fed cmo mice had marked alterations in their microbiome compared to the cmo mice fed with a normal low fat diet (LFD). Notably, the cmo mice on a LFD had relative enrichment of inflammation-associated microbes including Prevotella accompanied by reductions in Lactobacillus species, compared to those on a HFD [68]. Pro-IL-1β levels are upregulated in the cmo mice fed with a LFD compared to those on a HFD [68]. Fecal transplant of stool from the cmo on a LFD into the young unaffected cmo mice accelerated the development of osteomyelitis, whereas stool from the cmo fed with a HFD transplanted into the young unaffected cmo mice was associated with relative decreases in Prevotella and with relative protection from disease [68]. Although the fecal transplant experiments suggest that changes in the microbiome can drive the inflammatory bone phenotype, it remains a possibility that the changes in microbiome are secondary to metabolic changes. Regardless, it will be essential to determine the specific components in the diet that drive disease in the mouse, to determine if dysbiosis occurs in humans with CRMO, and to determine if this finding can be translated into a treatment for human CRMO. Data on the effect of diet on CRMO disease in humans is lacking. One author (PJF) cares for an individual with CRMO and celiac

Fig. 1 Diet-induced changes in the microbiome drives neutrophil production of biologically active IL-1β which causes bone inflammation in the Pstpip2-deficient cmo mouse

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disease who had a flare of osteomyelitis despite maintaining a gluten-free diet with suppression of TTG. One could implicate gluten in this patient’s disease pathogenesis yet this patient has an affected sister with CRMO but without clinical or serologic evidence of celiac disease. Identification of the genetic lesions, molecular mechanisms, and immunologic pathway(s) required for the development of non-syndromic CRMO not only will illuminate the pathogenesis of the destructive bone disease seen in CRMO but also will inform us about the pathogenesis of the disorders that frequently occur in individuals with a personal or family history of CRMO including psoriasis, Crohn’s disease, and inflammatory arthritis. Syndromic forms of human CRMO and data generated in the Pstpip2-deficient cmo mice identify IL-1β as the key disease associated cytokine. It is the neutrophil that hyperproduces IL-1β in the cmo mouse, and new data suggest that the level of IL-1β produced by neutrophils can be modulated by diet. The role of IL-1β, diet, and the microbiome in human CRMO needs further investigation as translation of these findings to the clinic has the potential for significantly altering treatment strategies (Fig. 1.)

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Acknowledgments PJF is supported by the National Institutes of Health Grant R01 AR059703.

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References

21.

1.

Hedrich CM, Hofmann SR, Pablik J, Morbach H, Girschick HJ (2013) Autoinflammatory bone disorders with special focus on chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 11:47 2. Stern SM, Ferguson PJ (2013) Autoinflammatory bone diseases. Rheum Dis Clin N Am 39:735–49 3. Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, Grote V, Diebold J, Jansson V, Schneider K, Belohradsky BH (2007) Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 46:154–60 4. Kahn MF, Chamot AM (1992) SAPHO syndrome. Rheum Dis Clin N Am 18:225–46 5. Giedion A, Holthusen W, Masel LF, Vischer D (1972) Subacute and chronic “symmetrical” osteomyelitis. Ann Radiol (Paris) 15: 329–42 6. Girschick HJ, Raab P, Surbaum S, Trusen A, Kirschner S, Schneider P, Papadopoulos T, Muller-Hermelink HK, Lipsky PE (2005) Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 64:279–85 7. Schultz C, Holterhus PM, Seidel A, Jonas S, Barthel M, Kruse K, Bucsky P (1999) Chronic recurrent multifocal osteomyelitis in children. Pediatr Infect Dis J 18:1008–13 8. Ferguson PJ, Brown DR, Sundel R, Killian J, El-Shanti HI (2005) Chronic inflammatory disorders in first and second degree relatives of children with chronic recurrent multifocal osteomyelitis. Arthritis Rheum 52:747 9. Sasaki T (1967) A case of osteomyelitis of the bilateral clavicles associated with pustulosis palmaris et plantaris. Rinsho Seikeigeka 2:333–7

22.

23. 24.

25.

26.

27. 28.

29.

30.

31.

Bjorksten B, Gustavson KH, Eriksson B, Lindholm A, Nordstrom S (1978) Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr 93:227–31 Bergdahl K, Bjorksten B, Gustavson KH, Liden S, Probst F (1979) Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica 159:37–45 Paller AS, Pachman L, Rich K, Esterly NB, Gonzalez-Crussi F (1985) Pustulosis palmaris et plantaris: its association with chronic recurrent multifocal osteomyelitis. J Am Acad Dermatol 12:927–30 Laxer RM, Shore AD, Manson D, King S, Silverman ED, Wilmot DM (1988) Chronic recurrent multifocal osteomyelitis and psoriasis—a report of a new association and review of related disorders. Semin Arthritis Rheum 17:260–70 Bognar M, Blake W, Agudelo C (1998) Chronic recurrent multifocal osteomyelitis associated with Crohn’s disease. Am J Med Sci 315:133–5 Bousvaros A, Marcon M, Treem W, Waters P, Issenman R, Couper R, Burnell R, Rosenberg A, Rabinovich E, Kirschner BS (1999) Chronic recurrent multifocal osteomyelitis associated with chronic inflammatory bowel disease in children. Dig Dis Sci 44:2500–7 Jo Y, Matsumoto T, Nagamine R (2001) A case of Crohn’s disease with leg pain. Br J Radiol 74:203–4 Carpenter E, Jackson MA, Friesen CA, Scarbrough M, Roberts CC (2004) Crohn’s-associated chronic recurrent multifocal osteomyelitis responsive to infliximab. J Pediatr 144:541–4 Assmann G, Simon P (2011) The SAPHO syndrome—are microbes involved? Best Pract Res Clin Rheumatol 25:423–34 Rozin AP (2009) SAPHO syndrome: is a range of pathogenassociated rheumatic diseases extended? Arthritis Res Ther 11:131 Assmann G, Kueck O, Kirchhoff T, Rosenthal H, Voswinkel J, Pfreundschuh M, Zeidler H, Wagner AD (2009) Efficacy of antibiotic therapy for SAPHO syndrome is lost after its discontinuation: an interventional study. Arthritis Res Ther 11:R140 Huber AM, Lam PY, Duffy CM, Yeung RS, Ditchfield M, Laxer D, Cole WG, Kerr Graham H, Allen RC, Laxer RM (2002) Chronic recurrent multifocal osteomyelitis: clinical outcomes after more than five years of follow-up. J Pediatr 141:198–203 Bjorksten B, Boquist L (1980) Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg (Br) 62:376– 80 Jurik AG (2004) Chronic recurrent multifocal osteomyelitis. Semin Musculoskelet Radiol 8:243–53 Pelkonen P, Ryoppy S, Jaaskelainen J, Rapola J, Repo H, Kaitila I (1988) Chronic osteomyelitis-like disease with negative bacterial cultures. Am J Dis Child 142:1167–73 King SM, Laxer RM, Manson D, Gold R (1987) Chronic recurrent multifocal osteomyelitis: a noninfectious inflammatory process. Pediatr Infect Dis J 6:907–11 Girschick HJ, Huppertz HI, Harmsen D, Krauspe R, MullerHermelink HK, Papadopoulos T (1999) Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing. Hum Pathol 30:59–65 Carr AJ, Cole WG, Roberton DM, Chow CW (1993) Chronic multifocal osteomyelitis. J Bone Joint Surg (Br) 75:582–91 Yu L, Kasser JR, O’Rourke E, Kozakewich H (1989) Chronic recurrent multifocal osteomyelitis. Association with vertebra plana [see comments]. J Bone Joint Surg Am 71:105–12 Manson D, Wilmot DM, King S, Laxer RM (1989) Physeal involvement in chronic recurrent multifocal osteomyelitis. Pediatr Radiol 20:76–9 Sharma M, Ferguson PJ (2013) Autoinflammatory bone disorders: update on immunologic abnormalities and clues about possible triggers. Curr Opin Rheumatol 25:658–64 Deutschmann A, Mache CJ, Bodo K, Zebedin D, Ring E (2005) Successful treatment of chronic recurrent multifocal osteomyelitis with tumor necrosis factor-alpha blockage. Pediatrics 116:1231–3

Semin Immunopathol 32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

47.

48.

Kerrison C, Davidson JE, Cleary AG, Beresford MW (2004) Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology (Oxford) 43:1246–51 Miettunen PM, Wei X, Kaura D, Reslan WA, Aguirre AN, Kellner JD (2009) Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 7:2 Simm PJ, Allen RC, Zacharin MR (2008) Bisphosphonate treatment in chronic recurrent multifocal osteomyelitis. J Pediatr 152: 571–5 Gleeson H, Wiltshire E, Briody J, Hall J, Chaitow J, Sillence D, Cowell C, Munns C (2008) Childhood chronic recurrent multifocal osteomyelitis: pamidronate therapy decreases pain and improves vertebral shape. J Rheumatol 35:707–12 Amital H, Applbaum YH, Aamar S, Daniel N, Rubinow A (2004) SAPHO syndrome treated with pamidronate: an open-label study of 10 patients. Rheumatology (Oxford) 43:658–61 Compeyrot-Lacassagne S, Rosenberg AM, Babyn P, Laxer RM (2007) Pamidronate treatment of chronic noninfectious inflammatory lesions of the mandible in children. J Rheumatol 34:1585–9 Just A, Adams S, Brinkmeier T, Barsegian V, Lorenzen J, Schilling F, Frosch P (2008) Successful treatment of primary chronic osteomyelitis in SAPHO syndrome with bisphosphonates. J Dtsch Dermatol Ges 6:657–60 Hofmann SR, Schwarz T, Moller JC, Morbach H, Schnabel A, Rosen-Wolff A, Girschick HJ, Hedrich CM (2011) Chronic nonbacterial osteomyelitis is associated with impaired Sp1 signaling, reduced IL10 promoter phosphorylation, and reduced myeloid IL10 expression. Clin Immunol 141:317–27 Hofmann SR, Roesen-Wolff A, Hahn G, Hedrich CM (2012) Update: cytokine dysregulation in chronic nonbacterial osteomyelitis (CNO). Int J Rheumatol 2012:310206 Hofmann SR, Morbach H, Schwarz T, Rosen-Wolff A, Girschick HJ, Hedrich CM (2012) Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression. Clin Immunol 145:69–76 Ferguson PJ, El-Shanti HI (2007) Autoinflammatory bone disorders. Curr Opin Immunol 19:492 Golla A, Jansson A, Ramser J, Hellebrand H, Zahn R, Meitinger T, Belohradsky BH, Meindl A (2002) Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3–18q22. Eur J Hum Genet 10:217–21 Safra N, Johnson EG, Lit L, Foreman O, Wolf ZT, Aguilar M, Karmi N, Finno CJ, Bannasch DL (2013) Clinical manifestations, response to treatment, and clinical outcome for Weimaraners with hypertrophic osteodystrophy: 53 cases (2009–2011). J Am Vet Med Assoc 242:1260–6 Safra N, Pedersen NC, Wolf Z, Johnson EG, Liu HW, Hughes AM, Young A, Bannasch DL (2011) Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations. Vet J 189:220–6 Crumlish PT, Sweeney T, Jones B, Angles JM (2006) Hypertrophic osteodystrophy in the Weimaraner dog: lack of association between DQA1 alleles of the canine MHC and hypertrophic osteodystrophy. Vet J 171:308–13 Grosse J, Chitu V, Marquardt A, Hanke P, Schmittwolf C, Zeitlmann L, Schropp P, Barth B, Yu P, Paffenholz R, Stumm G, Nehls M, Stanley ER (2006) Mutation of mouse Mayp/Pstpip2 causes a macrophage autoinflammatory disease. Blood 107: 3350–8 Ferguson PJ, Bing X, Vasef MA, Ochoa LA, Mahgoub A, Waldschmidt TJ, Tygrett LT, Schlueter AJ, El-Shanti H (2006) A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis. Bone 38:41–7

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60. 61.

62.

63.

Cassel SL, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, Iwakura Y, Shayakhmetov DM, Bassuk AG, Abu-Amer Y, Brogden KA, Burns TL, Sutterwala FS, Ferguson PJ (2014) Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A 111: 1072–7 Lukens JR, Gross JM, Calabrese C, Iwakura Y, Lamkanfi M, Vogel P, Kanneganti TD (2014) Critical role for inflammasomeindependent IL-1β production in osteomyelitis. Proc Natl Acad Sci U S A 111:1066–71 Chitu V, Ferguson PJ, de Bruijn R, Schlueter AJ, Ochoa LA, Waldschmidt TJ, Yeung YG, Stanley ER (2009) Primed innate immunity leads to autoinflammatory disease in PSTPIP2-deficient cmo mice. Blood 114:2497–505 Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM, Pelet A, Munnich A, Lyonnet S, Majeed HA, El-Shanti H (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42: 551–7 Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R (2009) An autoinflammatory disease with deficiency of the interleukin-1 receptor antagonist. N Engl J Med 360:2426–37 Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M, Broeckel U, Hessner MJ, Verbsky J (2009) An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 360: 2438–44 Al-Mosawi ZS, Al-Saad KK, Ijadi-Maghsoodi R, El-Shanti HI, Ferguson PJ (2007) A splice site mutation confirms the role of LPIN2 in Majeed syndrome. Arthritis Rheum 56:960–4 Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF, alGharbawy F, Majeed SA, al-Gazzar AH (1989) Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J Pediatr 115:730–4 Majeed HA, El-Shanti H, Al-Rimawi H, Al-Masri N (2000) On mice and men: an autosomal recessive syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia. J Pediatr 137:441–2 Majeed HA, Al-Tarawna M, El-Shanti H, Kamel B, Al-Khalaileh F (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160:705–10 Herlin T, Fiirgaard B, Bjerre M, Kerndrup G, Hasle H, Bing X, Ferguson PJ (2013) Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann Rheum Dis 72:410–3 Reue K (2009) The lipin family: mutations and metabolism. Curr Opin Lipidol 20:165–70 Donkor J, Zhang P, Wong S, O’Loughlin L, Dewald J, Kok BP, Brindley DN, Reue K (2009) A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. J Biol Chem 284: 29968–78 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015–25 Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of

Semin Immunopathol

64.

65.

66.

cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem 276:16683–9 Hwang D (2001) Modulation of the expression of cyclooxygenase2 by fatty acids mediated through toll-like receptor 4-derived signaling pathways. FASEB J 15:2556–64 Valdearcos M, Esquinas E, Meana C, Pena L, Gil-de-Gomez L, Balsinde J, Balboa MA (2012) Lipin-2 reduces proinflammatory signaling induced by saturated fatty acids in macrophages. J Biol Chem 287:10894–904 Goldbach-Mansky R (2012) Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic

autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 167: 391–404 67. Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA (2014) Inflammasome-independent regulation of IL-1family cytokines. Annu Rev Immunol 68. Lukens JR, Gurung P, Vogel P, Johnson GR, Carter RA, McGoldrick DJ, Bandi SR, Calabrese CR, Walle LV, Lamkanfi M, Kanneganti TD (2014) Dietary modulation of the microbiome affects autoinflammatory disease. Nature 516:246–249